Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents

Background: The last decade has seen development of numerous novel antipsychotic drugs with unique mechanisms including long-acting formulations for clinical use. A comparative assessment of these new drugs with each other and previous antipsychotics have not been performed with regards to risk for drug-induced movement disorders (DIMD). Methods: Medline was searched from January 2010 to February 2022 for primary research articles and review articles in English using the search terms “extrapyramidal” and “tardive” with individual drug names of novel antipsychotics. Results: We identified articles describing the risk of DIMD with 6 novel antipsychotics, 4 novel formulations, and 3 experimental antipsychotics. Both short- and long-term data generally showed comparable to lower risk of DIMD with novel antipsychotics and recent long-acting formulations compared to previously marketed antipsychotics. Discussion: Several novel antipsychotics, particularly lumateperone and pimavanserin, show promise in being able to treat psychosis while reducing the risk of DIMD. Long-acting paliperidone may reduce risk of DIMD while other long-acting injectable formulations of SGA have similar risk of DIMD compared to oral formulations. New drug targets for treating psychosis without dopamine blockade also show promise.


INTRODUCTION TO DRUG-INDUCED MOVEMENT DISORDERS (DIMD)
The association of antipsychotics with DIMD has been attributed primarily to their dopamine 2 receptor (D2R) blocking properties [1]. Acute DIMD refers to early-onset and reversible phenomena including akathisia, dystonia, parkinsonism, and tremor [2]. Tardive DIMD have a variable presentation, most commonly including stereotypy or chorea, but also dystonia, akathisia, myoclonus, tics, and tremor occurring at least weeks to months after drug exposure and often persisting despite drug cessation [1,3]. The prevalence of tardive syndromes among antipsychotictreated patients is estimated to be between 20-30%, with annual incidence significantly increased by exposure to first-generation antipsychotics (FGAs) versus secondgeneration antipsychotics (SGAs) of 5.4-7.7% versus 0.8-3% (p < 0.0001), respectively, as well as by patient age [4,5]. Although SGA use has reduced the incidence of DIMD compared to FGAs, the expansive marketing and prescription of SGAs may increase the absolute number of individuals at risk [6]. Understanding how novel antipsychotics influence risk of the development of acute and tardive DIMD is critical to reducing patient harm. Although comparisons between reported studies are constrained by differences in design, methodology, and sample populations, we herein descriptively review data on acute and tardive DIMD associated with novel antipsychotics that have received Food and Drug Administration (FDA) approval since 2010 in addition to drugs in development.

METHODS
In this review, we restricted medications discussed to antipsychotic agents approved by the FDA since 2010: brexpiprazole, cariprazine, lumateperone, lurasidone, pimavanserin, olanzapine-samidorphan (O-S), longacting injectable (LAI) risperidone, LAI aripiprazole, LAI paliperidone, transdermal asenapine, and inhaled loxapine. The terms in the Medline database searched from January 2010 to February 2022 and the identified additional articles through reference review are indicated in Supplementary Table 1. Articles reporting original interventional or observational studies addressing the incidence, prevalence or risk of antipsychotic-related DIMD were included in the review. Articles unavailable in English or exclusively focusing on preclinical data were excluded. Case reports, non-systematic reviews and position/editorial papers were not cited directly unless reporting relevant data. Sample sizes and results of statistical testing demonstrating significant differences between groups in cited studies are indicated within the text when reported in original studies.

INCIDENCE OF DIMD WITH NOVEL ANTIPSYCHOTICS A. BREXPIPRAZOLE i. Mechanism and Unique Features
Brexpiprazole's mechanism of action in treatment of psychosis and treatment-resistant depression (TRD) is primarily through partial agonism at D2Rs and 5-HT 2A Rs with antagonism at 5-HT 2A Rs [7]. Brexpiprazole has less partial agonism at the D2R relative to aripiprazole but has higher 5-HT2A antagonism which may explain its lower likelihood of inducing DIMD. Aripiprazole's higher potency in inhibiting acetylcholinesterase activity may also play a role in its propensity to cause more DIMD relative to brexpiprazole [8]. It was approved for use in schizophrenia and as adjunctive treatment of depression in 2015 [9].
ii. Incidence of DIMD The most common acute DIMD associated with brexpiprazole is akathisia occurring within three weeks of drug initiation [9]. In two double-blind, randomized control trials (DBRCTs) evaluating brexpiprazole for treatment of schizophrenia (n = 636, 674), there was no significant difference in acute DIMD as measured by multiple scales, including the Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), and the Drug-Induced EPS Scale (DIEPSS), at doses up to 4mg/day after 6 weeks relative to baseline or placebo [9,10]. Other studies (n = 282, 379) have shown higher rates of akathisia relative to placebo (6.5-13.5% versus 1.0-7.1%) at doses of brexpiprazole greater than 2 mg/ day [11,12]. A six-week phase III trial (n = 459) for acute schizophrenia episodes in Japan demonstrated 9-11% of individuals in treatment groups needed medication for parkinsonism relative to 4% in the placebo group while akathisia (1.7-5.3% versus 6.9%) was less frequent in the treatment groups [13]. A 52-week open-label Japanese trial (n = 150) for maintenance treatment of schizophrenia demonstrated that the rates of akathisia and tremor to be 8.5% and 4.3%, respectively [11]. Another one-year DBRCT (n = 524) for maintenance treatment of schizophrenia demonstrated no significant increase in acute DIMD based on motor rating scales with equal rates of akathisia (1.0%) but higher rates of tremor (3.0% versus 1.0%) relative to placebo [14]. A meta-analysis of three brexpiprazole (2-4 mg/day) RCTs (n = 1444) demonstrated no significant differences in SAS, BARS, or reported DIMD compared to placebo [15].
In a 52-week open-label extension of phase III trials for schizophrenia, only one of 1072 individuals developed TD, classified as moderately severe [18]. One case report demonstrated copulatory dyskinesia in association with brexpiprazole use [19]. While most data suggests that DIMD from brexpiprazole is not severe, one case report described severe parkinsonism [20]. One case report using brexpiprazole in the treatment of Parkinson's disease psychosis demonstrated no AE [21]. Overall, akathisia is the most common DIMD with brexpiprazole but rates of DIMD in general are low.

iii. Comparison to previous SGAs
Relative to adjunctive aripiprazole use (n = 353, 677), brexpiprazole showed lower SAS and BARS scores and a lower incidence of akathisia in TRD [12,16]. In an open-label RCT for schizophrenia comparing aripiprazole (n = 33) to brexpiprazole (n = 64), DIMDs were twice as likely in the aripiprazole-treated group, most commonly akathisia (21.2% versus 9.4%), without significant differences in SAS or BARS [22]. In a small cohort of 37 Japanese individuals with schizophrenia or schizoaffective disorders, switching from other SGAs to brexpiprazole significantly improved scores by 1 point on average on the DIEPSS (p = 0.008) after eight weeks.

B. CARIPRAZINE i. Mechanism and Unique Features
Relative to aripiprazole and brexpiprazole, cariprazine has a tenfold higher affinity for D3Rs with partial agonism at D2Rs and 5-HT 1A Rs [27]. The D3R is preferentially expressed in brain regions, such as the ventral striatum, that regulate reward and motivation rather than motor control which could explain its proposed efficacy in the treatment of negative symptoms in schizophrenia [28]. It is FDA approved for the treatment of schizophrenia and bipolar disorder (BPD) [29].
In pooled analyses (n = 1407), TD was rare in the shortterm, occurring in less than 0.5% of individuals over 7-9 weeks [46]. A systematic review of nine RCTs (n = 4324) in patients with BPD, schizophrenia, and MDD, cariprazine had a significantly higher risk of akathisia (relative risk [

C. LUMATEPERONE i. Mechanism and Unique Features
Lumateperone is a first-in-class medication that simultaneously acts at serotonergic, dopaminergic, and glutamatergic receptors [49]. It was FDA approved for use in schizophrenia in 2020 but is also under investigation for mood disorders [49,50]. At 5-HT 2A Rs, it acts as an antagonist with 60-fold higher affinity than at D2Rs, where it acts pre-synaptically as a partial agonist and postsynaptically as an antagonist, which is proposed to reduce its risk of causing DIMD [49]. By contrast, other SGAs like risperidone and olanzapine have a 12:1 affinity for binding of D2Rs and 5-HT 2A Rs. By inhibiting a serotonin transporter, it also increases phosphorylation of GluN2B receptors in mesolimbic pathways. The unique mechanism of this drug suggests that it could be useful at low doses for sleep and agitation reduction with antipsychotic and antidepressant effects at higher doses [50].

ii. Incidence of DIMD
A phase II DBRCT (n = 335) using doses of 60-120 mg/day of lumateperone in acute exacerbation of schizophrenia demonstrated AEs of akathisia in 2% of subjects, which was comparable to placebo. There were no significant change in SAS, AIMS, or BARS over 28 days [51]. Indeed, phase III DBRCTs (n = 450) and open label studies (n = 1481) with 40-60 mg/day confirm that the rates of acute DIMD are similar to placebo for as long as 12 months [52,53]. In pooled studies (n = 381, 1073), lumateperone showed similar rates of acute DIMD and use of medications to treat DIMD compared to placebo and lower rates than risperidone (4 mg/day) [54,55]. No clear reports of tardive syndromes associated with lumateperone have been published.

D. LURASIDONE i. Mechanism and Unique Features
Lurasidone is approved for acute and maintenance treatment of schizophrenia and for treatment of bipolar depression [56]. It acts via potent antagonism at 5-HT 7 R and partial agonism at 5-HT1 A Rs mediating cognitive and antidepressant effects while having significant affinity for 5-HT 2A Rs and D2Rs [56].
A 24-week open-label extension trial (n = 813) for lurasidone's adjunctive use in bipolar depression showed rates of overall DIMD and akathisia as high as 10.7% and 8.1%, respectively, with these AEs found more commonly in adjunctive therapy rather than monotherapy arms [69]. Another 28-week open label extension trial (n = 413) showed akathisia and parkinsonism in 18.2% and 7.3%, respectively [70]. Discontinuation rate of lurasidone due to akathisia was less than 3% in these studies [69,70]. A DBRCT (n = 496) with placebo control, using a 20-week stabilization phase and subsequent 28 week treatment period in BPD showed similar rates of DIMD as other longterm studies [71]. Case reports have identified individuals with TD, drug-induced parkinsonism, rabbit syndrome, and laryngospasm with lurasidone-exposure [72][73][74][75][76].

E. PIMAVANSERIN i. Mechanism and Unique Features
Pimavanserin is a 5-HT 2A R inverse agonist and was approved for use in Parkinson's disease (PD) psychosis (PDP) in 2016 at a dose of 34 mg daily [84]. Because of its unique selectivity for this receptor, located on multiple types of excitatory neurons, it has benefit in psychosis without causing antidopaminergic side effects [85]. Decreasing signaling through the 5-HT 2A receptor may impact psychosis through decreasing dopamine release in the nucleus accumbens and in ventral tegmental neurons that project to frontal cortical and limbic regions [86].

ii. Incidence of DIMD
In placebo-controlled DBRCTs (n = 60, 199) in PDP, AEs were similar between placebo and treatment groups [86,87]. Use of pimavanserin in conjunction with subtherapeutic doses of risperidone or haloperidol in psychosis in chronic schizophrenia did not show differences in motor AEs or as measured by SAS or BARS compared to placebo (n = 423) [84]. Very preliminary evidence (n = 403) for efficacy and similar tolerability in adjunctive treatment of negative symptoms in schizophrenia also exists without increase in DIMD while other studies are ongoing [88][89][90][91].
No studies have specifically cited or examined the risk of tardive syndromes with pimavanserin.

iii. Comparison to previous SGAs
No studies were identified that have evaluated the risk of DIMD in pimavanserin relative to SGAs.

F. OLANZAPINE-SAMIDORPHAN (O-S) i. Mechanism of action
Olanzapine is an SGA that antagonizes 5-HT 2A/2C Rs, 5-HT 6 Rs, D1-4Rs, histamine-1 receptors (H1Rs) and α 1adrenergic receptors and has been associated with weight gain and propensity for development of metabolic syndrome [92]. Samidorphan has been shown to alter glucose homeostasis and has been used clinically to mitigate weight gain caused by olanzapine [92]. O-S was approved in 2021 for treatment of schizophrenia and BPD [92].

A. LAI ANTIPSYCHOTICS AND OTHER NOVEL FORMULATIONS
LAI antipsychotics were developed to improve poor medication adherence observed with oral formulations [99]. Studies looking at pooled data comparing oral versus LAI formulations have had mixed results with some showing no difference in DIMD whereas others have suggested higher rates with LAIs [100][101][102]. We review below evidence regarding incidence of acute DIMD and tardive syndromes in recently developed LAIs and other novel drug formulations.
i. LAI Risperidone

Mechanism and Unique Features
LAI risperidone was the first SGA available in depot form and is now available in intramuscular and subcutaneous formulations of varying dosages and half-lives [103]. LAI risperidone has lower peak levels and fluctuations in levels than oral formulations [104]. Risperidone is an antagonist at D2Rs greater than D1Rs and has inverse agonist activity at 5-HT 2A/2C Rs [105].

Incidence of DIMD
Both short (n = 49, 264, 804) and long term (up to one year) studies (n = 215) in acute and maintenance treatment of schizophrenia and BPD have demonstrated that rates of acute DIMD, ranging from 3-23% were not significantly different between LAI risperidone and placebo and there were low not significantly different rates of discontinuation (<1%) due to DIMD [ ii. LAI Paliperidone palmitate

Incidence of DIMD
A 12-week phase II DBRCT (n = 197) showed increased parkinsonism relative to placebo (8% versus 1%) but no other increase in DIMD [115]. A larger phase III DBRCT (n = 514) with the monthly formulation showed similar rates of DIMD, most commonly parkinsonism (5-6%), to placebo and decreased use of anti-DIMD medications from 30% before to 6% after the double-blind period but no significant change in SAS, BARS, or AIMS scales [114]. Another 12-week DBRCT (n = 305) with the 3-month formulation showed increased rates of akathisia, 4%, relative to placebo, 1%, but no difference in other rates of DIMD [116]. Other studies (n = 197-951) in schizophrenia and schizoaffective disorder with LAI paliperidone also showed low rates of DIMD [117,118]. These results are similar to studies (n = 305, 514) with oral paliperidone and one pooled analysis (n = 3121) suggest relatively decreased DIMD rates with LAI paliperidone (anti-DIMD medication 17% versus 12%, p = 00035; BARS -0. A pooled analysis (n = 3743) looking specifically at rates of TD showed low rates <0.2% regardless of administered formulation [120]. A case of unmasked parkinsonism has been reported with LAI paliperidone use persisting after drug cessation [121]. Case reports of tardive dystonia, TD, and parkinsonism, with LAI paliperidone are also found in the literature [122][123][124].

ii. LAI Aripiprazole 1. Mechanism and Unique Features
Aripiprazole monohydrate is a powder that is mixed with water for monthly intramuscular injections [131]. Aripiprazole lauroxil is administered from prefilled syringes ranging from 441 to 882 mg every 4-8 weeks intramuscularly [131]. Aripiprazole acts as a partial agonist at 5-HT 1A Rs and as an antagonist at 5-HT 2A Rs with a complex interaction at D2Rs [132]. At D2Rs, this drug acts as a partial antagonist at high extracellular dopamine concentrations and as a partial agonist at low extracellular dopamine concentrations [133].

Incidence of DIMD
Short-term studies (n = 340, 623) using LAI aripiprazole in acute schizophrenia episodes did not show significant changes in motor scales but some studies showed a higher rate of akathisia relative to placebo (11% versus 4%) [134,135]. In a 52 week, placebo-controlled DBRCT (n = 710) of maintenance treatment of schizophrenia using LAI aripiprazole, rates of overall DIMD, akathisia, dyskinesia, dystonia, and parkinsonism were 14.9% vs 9.7%, 5.6% vs 6.0%, 0.7% vs 1.5%, 8.2% vs 3.0%, for treatment versus placebo, respectively, with no significant difference in change in AIMS, SAS, or BARS which is similar to data from other long term studies [136]. Frequency of anticholinergic therapy for DIMD in these studies was 16.7% versus 10.4% in placebo [135,136]. A meta-analysis (n = 986) comparing tolerability of LAI versus oral aripiprazole showed no difference in DIMD [112]. A systematic review (n = 4796) comparing various LAIs demonstrated that aripiprazole had a lower odds of DIMD compared to risperidone or paliperidone, but this effect was not significant due to high variability [130]. No reports of tardive syndromes related to LAI aripiprazole were found in the literature.

Incidence of DIMD
A phase III clinical trial (n = 253) showed no increase in motor scales assessing DIMD [139]. Data from this phase III DBRCT using sublingual asenapine showed akathisia and overall DIMD rates as high as 7.7% and 10%, respectively, during a 12-16-week open label period (n = 549) and 1.6% and 2.4%, respectively, during the 26-week doubleblind phase (n = 253) relative to 0.8% in the placebo group [139]. Other studies (n = 80-532) in both schizophrenia and bipolar mania or mixed episodes showed similar rates of these AEs and minimal changes in motor rating scales [138]. No reports were found of tardive syndromes are associated with transdermal asenapine.

V. Inhaled loxapine 1. Mechanism and Unique Features
Loxapine has existed as an oral formulation for over 40 years and also as an intramuscular formulation for the treatment of agitation [140]. The inhaled formulation (10 mg per inhalation) was approved by the FDA in 2012 for agitation in schizophrenia and mania and can achieve peak concentrations in 2-5 minutes with a half-life of 4 hours [140]. Structurally like clozapine it has postsynaptic antagonism at D2R and 5-HT 2A R [140].

Incidence of DIMD
In clinical trials (n = 129-344) for agitation in bipolar mania and schizophrenia, inhaled loxapine was not associated with any significant increase in DIMD [141]. Benztropine was given for one individual with acute akathisia and another with acute dystonia (jaw and oculogyric) which resolved symptoms in both cases. Oral formulations of loxapine have been associated with TD, tardive dystonia, and other DIMD at rates similar to SGAs [141]. However, the risk of tardive syndrome is likely rare with intended use of inhaled loxapine as rescue therapy.

AGENTS WITH NOVEL MECHANISMS UNDER INVESTIGATION
Three novel classes of antipsychotics are currently under investigation whose mechanisms of action have the potential to obviate DIMD. Uloturant, a trace amineassociated receptor 1 (TAAR1) agonist, is currently in Phase 3 clinical trials for schizophrenia [142]. TAAR1s are G-protein coupled receptors expressed in multiple brain regions including the ventral tegmental area and the dorsal raphe nucleus, which allow for modulation of dopaminergic and serotonergic pathways improving positive schizophrenic symptoms and sleep [142]. While it has agonist activity at 5-HT 1A Rs, it does not have antagonism at D2 or 5-HT 2A Rs which is thought to improve its tolerability [142]. Early studies have not shown a risk of DIMD as expected from data in preclinical models with AEs most commonly being somnolence and GI symptoms [143].
Roluperidone is a high-affinity 5-HT 2A antagonist and σ2R antagonist [91]. Early trials have shown modest clinical efficacy without increased DIMD which is unsurprising given its lack of D2R antagonism [144]. Common side effects included headache, asthenia, and somnolence [91]. Finally, xanomeline is a selective M1 and M4 muscarinic receptor agonist [145]. While this drug has no significant direct binding to dopamine receptors, preclinical models demonstrate functional dopaminergic antagonism particularly in the ventral tegmental area [146]. Clinical trials have shown efficacy in schizophrenia with side effects mainly consisting of nausea, vomiting, gastrointestinal distress, and hypersalivation [145,147]. Notably, there were no DIMD-related AEs [145,147]. Ongoing studies will help better define the efficacy and tolerability of these medications.

SUMMARY
The decision to select an antipsychotic for treatment depends on an informed risk-benefit analysis of each individual patient's condition and needs, including consideration of efficacy and a range of potential side effects. Systematic reviews and meta-analyses show that in general, FGAs and SGAs, have comparable efficacy with differences that are on a continuum rather than discrete [148,149]. Research and development of antipsychotic drugs has largely been driven by the goal of eliminating adverse DIMD, especially irreversible tardive syndromes, while preserving antipsychotic effectiveness. The recent novel antipsychotics work through various mechanisms including greater serotonergic relative to dopaminergic antagonism, dose-dependent partial D2R agonism, and D3R antagonism [7,27,56]. These mechanisms allow for efficacy in psychosis while reducing incidence of DIMD (Table 2). Lumateperone and pimavanserin have a significantly lower risk of DIMD and tardive syndromes than previous antipsychotics, although relatively less data are currently available for these new agents. Relative to previous SGAs, brexpiprazole has a reduced risk of overall DIMD with increased risk of akathisia. Cariprazine and lurasidone have comparable rates of DIMD relative to previous SGAs with the former having a higher relative rate of akathisia.
LAI risperidone and LAI aripiprazole have similar rates compared to oral formulations. In general, alternate formulations of antipsychotics do not seem to change risk of DIMD. In the future, current drugs in the pipeline of research and development that further spare dopamine signaling suggest antipsychotic strategies that could promise separation from the intertwined and heretofore inevitable risk of acute and tardive DIMD.
Tardive syndromes with novel antipsychotics are reported to be overall rare in the trials reviewed here. However, there are major limitations that must be considered in the interpretation of this data. Most clinical trial designs include limited follow-up, at most a year; yet TD can take years to manifest, and thus may be underestimated in typical clinical trials. Furthermore, variable prior use of antipsychotics and inconsistent washout periods of prior antipsychotics complicates